CH627757A5 - Process for the preparation of cephalosporin derivatives and their salts - Google Patents

Description

The invention relates to a process for the preparation of the new compounds of general formula I.

R -N -

w r '

ca2s

COOH

rN_ï

(I)

CcH2) n ~ NHS03H

in the

W is a hydrogen atom or the methoxy group and R1 is one of the acyl residues

O

II

X-CH-C-,

A

O

II

Y-CH2-C- or O

Z-S (0) m-CH2-C-

where X represents a thienyl, dihydrophenyl, phenyl or phenyl radical substituted by a hydroxyl, hydroxymethyl, formamido, ureido or carboxymethylamino group,

A represents -NH2, -OH, -COOH or -SO3H or, if X represents the phenyl group, represents the formyloxy group,

Y represents a thienyl, tetrazolyl, Sydnon, cyano or amino-methylphenyl group,

45 Z represents a methyl, trifluoromethyl, trifluoroethyl, cyano-methyl or pyridyl group,

m has the value 0 to 2 and n has the value 2 to 5,

as well as their salts, in particular their pharmacologically acceptable salts, and their esters.

The carboxyl group in the 4-position of the compounds of the general formula I can easily be esterified by customary processes. Examples of such esters are simple alkyl and aryl esters, as well as esters that are easily split in the body, creating the original acid. Examples of such esters are indanyl, pivaloylo-methyl, acetoxymethyl, propionyloxymethyl, glycylo-methyl, phenylglycyloxymethyl and thienylglycyloxy-methyl esters. If A denotes the group -COOH, this group can be esterified in a similar manner. The preparation of the aforementioned esters is also an object of the invention.

Compounds of the general formula I in which n has the value 2 are preferred.

65 The compounds of general formula I can be divided into a group of compounds of general formula Ia and a further group of compounds of general formula Ib:

627757

4th

R -N

(la)

N - N

I.

(CH,) -NHSO ^ H / n -j

R1 ^

(Xb)

In the formulas la and Ib, the individual symbols have the aforementioned meaning.

Preferred compounds of the general formula Ia and Ib are those in which n has the value 2, X the phenyl group, A the amino or hydroxyl group, Y the thienyl or tetrazolyl group, Z the trifluoromethyl group and m the value 0. Specific examples of the 7-acyl substituents (R'NH) in the compounds of general formulas Ia and Ib are given below:

a-hydroxyphenylacetamido,

a-aminophenylacetamido,

a-amino-4-hydroxyphenylacetamido,

Trifluoromethyl acetamido,

Methylthioacetamido,

a-carboxythienylacetamido,

a-carboxyphenylacetamido,

a-sulfophenylacetamido,

a-amino-4-carboxymethylaminophenylacetamido,

2-aminomethylphenylacetamido,

3-Sydnonacetamido,

Tetrazolylacetamido,

Thienylacetamido,

2,2,2-trifluoroethylsulfinylacetamido,

Cyanoacetamido,

Methylsulfonylacetamido,

Cyanomethylthioacetamido, and

4-pyridylthioacetamido.

Specific examples of compounds of the general formula Ia are:

7-D-mandelic acid amido-3- [1- (2-sulfaminoethyl) tetrazole-5-

ylthiomethyl] -3-cephem-4-carboxylic acid,

7- (2-thienylacetamido) -3- [l- (2-sulfaminoethyl) tetrazole-5-

ylthiomethyl] -3-cephem-4-carboxylic acid,

7- (l-tetrazolylacetamido) -3- [l - (2-sulfaminoethyl) -tetrazole-

5-ylthiomethyl] -3-cephem-4-carboxylic acid and 7-trifluoromethylthioacetamido-3- [l- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid.

Examples of compounds of the general formula Ib are:

25 7a-methoxy-7ß- (2-thienylacetamido) -3- [l - (2-sulf-

aminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid,

7a-methoxy-7ß-trifluoromethylthioacetamido-3- [l- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carbon-30 acid,

7β-D-mandelic acid amido-7a-methoxy-3- [l- (2-sulfamino-ethyl) -tetrazol-5-ythiomethyl] -3-cephem-4-carboxylic acid and 7a-methoxy-7ß- (l-tetrazolylacetamido) -3 - [1- (2-sulfamino-ethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid.

35

40

45

50

55

60

65

Cephalosporin derivatives with the aforementioned acyl substituents in the 7-position are known. Corresponding compounds with various S-heterocyclothio-methyl groups (-CHiSHet) in the 3-position of the cephem nucleus are also known. However, the compounds according to the invention with 3- (sulfaminoalkyl-substituted-tetrazolyl) thiomethyl radicals are not known.

The method according to the invention is defined in claim 1.

The starting compounds of the general formula II, in which W is a hydrogen atom, can be prepared by acylating 7-aminocephalosporanic acid with an appropriately protected acylating agent and then removing the protective group which may be present. The carboxyl group of the acylating agent is activated by conventional methods, for example by converting it to the mixed anhydride, acid chloride, acid imidazolide or to an activated ester. In addition, a reagent such as dicyclohexylcarbodiimide can be used, provided that the carboxyl group of the cephem nucleus has an easily removable protecting group, such as benzethyl, tert-butyl, trichloroethyl, benzyl, benzyloxy methyl, p, Methoxybenzyl- or p-nitrobenzyl ester group is protected. When A represents an amino group, the a-amino group of the acylating agent is preferably replaced with an easily removable, customary protecting group, such as a tert-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl group, as a methyl acetoacetate adduct or by the like before the acylation Peptide synthesis usual groups, protected.

The protecting groups can be removed by conventional methods, for example using trifluoroacetic acid, if tert-butyl or tert-butoxycarbonyl protective

5

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groups can be used. The salt obtained is converted into the zwitterion or the free acid by means of an ion exchange resin such as a polystyrene-amine ion exchange resin (Amberlite IR-45) or by alkalizing an aqueous salt solution.

The starting products used as acylating agents are either known or are prepared by known processes.

The sulfaminoalkyltetrazole-thiols of the general formula III can be obtained by reacting the corresponding 1-amino-alkyl-5- (2,4-dinitrophenylthio) -tetrazole derivatives (prepared from 2,4-dinitrofluorobenzene and a 1-acetamidoalkylfluorobenzyl and an l-acetamidoalkyltetrazole -5-thiol with subsequent acid hydrolysis of the acetamido residue) with a sulfur trioxide-trimethylamine complex with subsequent elimination of the 2,4-dinitrophenyl protective group. The l-acetamidoalkyltetrazole-5-thiols are prepared by reacting an acetamidoalkyldithiocarbomat, such as methyl 2-acetamidoethyldithiocarbomat, with an azide, such as sodium azide. The acetamidoalkyl dithiocarbomates are prepared by treating an N-aminoalkylacetamide such as N- (2-aminoethyl) acetamide with carbon disulfide and an alkyl halide such as methyl iodide in the presence of a base such as triethylamine.

The 7a-methoxy-7β-acylaminocephalosporanic acids or their salts are either known or can be prepared by known processes.

Certain compounds of the general formula I are capable of salt formation, for example with alkali metals, such as sodium or potassium, alkaline earth metals, such as calcine, or with the ammonium cation. If A in the general formula I denotes an amino group, the compounds can be present as zwitterions or salts with acids or bases. The salts can be prepared by customary processes using a wide variety of non-toxic, pharmacologically acceptable acids or bases. The invention also relates to the salts of the compounds of the general formula I, II and III.

Of the compounds of general formula I in which R1 is the rest

O

II

X-CH-C-

A

means, because of the asymmetric a-carbon atom in the 7-acetamido group, optical isomers exist. Depending on whether a racemic or optically active acid is used as the acylating agent, racemic or optically active products are obtained. The optically active acids can easily be prepared from the racemic compounds by separation by customary methods, for example by fractional crystallization of a salt with an optically active acid or base. The invention relates to all isomers, including separate isomers and mixtures thereof.

The compounds of general formula I, i. H. Both compounds of the general formulas Ia and Ib have an antibacterial action against gram-positive and gram-negative microorganisms. The minimum inhibitory concentrations (MIC) for in vitro tests are in the range from 0.2 to> 200 jig / ml.

Table I below provides test results for certain compounds of the invention. Table II provides information about the in vivo protection of mice (ED? O). Table III lists the compound names of the individual compounds.

Table I

In vitro minimum inhibitory concentrations, µg / ml

bacteria

Connect

dung no.

1

2nd

3rd

4th

S. aureus HH 127

3.1,

3.1

1.6

3.1

1.6

S. aureus SK 23390

0.8,

0.8

0.4

3.1

1.6

S.villaluzSK 70390

50,

200

25th

> 200

> 200

Strep. faecalis HH

100,

50

12.5

50

100

34358

E. coli SK 12140

0.8,

0.8

3.1

0.8

0.8

E. coli HH 33779

3.1,

1.6

12.5

0.8

1.6

Adhesive, pneumo. SK

1.6,

0.8

3.1

0.8

0.8

4200

Adhesive, pneumo. SK

0.4,

0.2

0.8

0.4

0.2

1200

Salmonella ATCC

0.2,

1.6

12.5

0.4

0.4

12176

Shigella HH117

0.4,

0.2

-

0.4

0.8

Pseudo. aerug. HH 63> 200,

> 200

> 200

> 200

> 200

Serratia marc. ATCC

100,

100

> 200

200

100

13880

Proteus morgani 179

1.6,

3.1

> 200

200

> 200

Entero. aerog. ATCC

50,

6.3

25th

3.1

6.3

13048

Entero. cloacae HH

1.6,

1.6

6.3

0.8

1.6

31254

Table II

In vivi-ED5o, mg / kg

Connection no.

E.coliSK 12140

Adhesive, pneumo. SK 4200

s.c.

p.O.

s.c.

p.o.

1

0.46

50

0.46

2nd

1.02

> 50

-

3rd

1.56

-

-

4th

1.82

50

-

Table III

Connection No. Name

1 7-D-mandelic acid amido-3- [l - (2-sulfamino-ethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

2 7- (2-Thienylacetamido) -3- [l - (2-sulfamino-ethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

3 7- (1 -T etrazolylacetamido) -3 - [1 - (2-sulfa-minoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

4th 7-trifluoromethylthioacetamido-3- [1- (2-

sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

Like other cephalosporins, the compounds of general formula I can be processed and administered to medicinal products. Administration can be by parenteral injection, for example, subcutaneously, intramuscularly or intravenously. The injection of sterile solutions or prepared accordingly

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10th

15

20th

25th

30th

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50

55

60

65

627757 6

Suspensions containing a cephalosporin penetrate the precipitate is dried to dryness of the general formula I in an effective, not evaporated. The residue obtained with methanol toxic amount is preferred. The dose unit is offset. The solid material formed during scratching is preferably filtered off by injection, 100 to 1000 mg. The methanol filtrate is 400 mg to 6 g by adding a 5 per total daily doses. The exact doses of solution of sodium methylate in methanol depend on the age and weight of the patient and brought to pH 11.3, stirred for 1 hour, filtered and treating the infection. These doses can be diluted by a specialist with 300 ml of diethyl ether. The solid obtained is filtered off based on the information given here compared to and the filtrate is evaporated to dryness. The residue obtained, determined from the known data of conventional cephalosporins, is treated with 95 percent ethanol. 10 rubbed to initiate crystallization. The solid product The examples illustrate the invention. is filtered and dissolved in methanol. The methanol solution is concentrated to a volume of 10 ml, with 75 ml of 95%

Example 1 diluted ethanol and again to a volume of

7-D-mandelic acid amido-3- [l- (2-sulfominoethyl) -tetrazole- 5 ml concentrated. The disodium salt of l- (2-sulfo-

5-ylthiomethyl] -3-cephem-4-carboxylic acid is aminoethyl) -tetrazol-5-thiol, mp 122 to 127 ° C.

A solution of 20.4 g (0.20 mol) of N- (2-aminoethyl) acetamide in 200 ml of 95 percent ethanol is mixed with 27.9 ml of C3H5N5O3S2.2 Na • 1.5 H2O (0.20 mol) Triethylamine and 12.0 ml (0.20 mol) of carbon disulphide. An exothermic reaction occurs under reflux: C 12.16 H 2.72 N 23 64. The mixture is then cooled to ambient temperature within IV2 20 ° C. 12.25 H 2.98 N 23 77 hours. 28.4 g (0.20 mol) of methyl iodide are then added, an exothermic reaction again occurring. After 13 hours the solution of the disodium salt of 1- (2-sulfamino-

The reaction mixture was evaporated to dryness. The ethyl) -tetrazole-5-thiol obtained in water is dissolved in a residue solid with Amberlite in 200 ml of water. The aqueous column of 25 IR-12 OH ion exchange resin was added.

Solution is extracted twice with 250 ml of ethyl acetate each. After lyophilization, 1 - (2-sulfaminoethyl) -

here. The extracts are combined, with sodium thiosulfate tetrazole-5-thiol.

shaken, dried over magnesium sulfate and a mixture of 2.71 g (0.006 mol) sodium salt of

Evaporated to dryness. This gives methyl 2-acetamidoethyl-7-D-mandelic acid amidocephalosporanic acid and 1.18 g of dithiocarbamate. 30 (0.004 mol) disodium salt of 1- (2-sulfaminoethyl) -

A solution of 38.4 g (0.198 mol) of methyl 2-acetamido-tetrazole-5-thiol in 30 ml of water is diluted with 10%

Ethyldithiocarbamate in 100 ml 95% ethanol is aqueous sodium hydroxide solution and then with a solution of 13.5 g (0.208 mol) sodium azide in 100% 5% aqueous sodium hydrogen carbonate solution.

ml of water are added. The reaction mixture is added for 24 hours, resulting in a pH of 7.3. The mixture is heated under reflux, then cooled and the mixture is then concentrated to half the volume under reduced pressure for 2 hours and 40 minutes. heated to 70 ° C, then cooled, with acetic acid

The solution is cooled to 15 ° C. and covered with 50 ml of 6N ethyl acetate, and 3N hydrochloric acid is added to bring the pH to formic acid. The acidic solution is filtered. The filtrate 2.5 acidified and extracted 2 times with ethyl acetate,

is concentrated to about 100 ml and to initiate the crystallization. The aqueous phase is neutralized to pH 7.0,

installation cooled to 5 ° C. The crystallized 1- (2-acetami- 40 by using a 10% aqueous sodium hydroxide solution.

diethyl) tetrzol-5-thiol is filtered off; F. 139 to 139.5 ° C. solution and then a 5 percent aqueous sodium

Additional quantities of product are added through continuous hydrogen carbonate solution. Then XAD-7-

Extraction of the filtrate with ethyl acetate resin using water and methanol as elu

receive. chromatographed. After removing the

A solution of 9.3 g (0.050 mol) of 2,4-dinitrofluorobenzene 45 methanol under reduced pressure is lyophilized in the fractions obtained in 50 ml of acetone to give a solution of 9.35 mg (0.050 chromatography)

Mol) 1 - (2-acetamidoethyl) -tetrazole-5-thiol and 6.85 ml receives the disodium salt of 7-D-mandelic acid amido-3- [l-

(0.050 mol) triethylamine added to 100 ml acetone. The (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-car-

The reaction mixture is stirred for 1 hour. The solid acid formed.

The material is filtered off and recrystallized from acetonitrile. 50

L- (2-Acetamidoethyl) -5- (2,4-dinitrophenylthio) - Ci9Hi9N70sS3.2Na- 3 H2O is obtained

tetrazole from F. 197 to 198 ° C. calc .: C 34.08 H 3.76 N 14.64

A mixture of 6.5 g (0.02 mol) of l- (2-acetamidoethyl) - found: C 34.56 H 3.25 N 13.96 5 (2,4-dinitrophenylthio) -tetrazole, 100 ml 12 n hydrochloric acid and

100 ml of 95 percent ethanol is 41 A hours under 55 An aqueous solution of the disodium salt of 7-D-man-

Reflux heated. After evaporation of the middle acid-3- [l - (2-sulfaminoethyl) -tetrazol-5-ylthio-

The rubbery residue krimethyl] -3-cephem-4-carboxylic acid obtained to dryness is

installed after adding ethanol. This gives a column packed with 1- (2-amino-lite IR-120H ion exchange resin),

ethyl) -5- (2,4-dinitrophenylthio) tetrazole hydrochloride from which gives the title compound.

F. 217 to 219 ° C (decomposition). 60

A solution of 3.5 g (0.01 mol) of l- (2-aminoethyl) -5- (2,4- Example 2

dinitrophenylthio) tetrazole hydrochloride in 30 ml of water 7- (2-thienylacetamido) -3- [l- (2-sulfaminoethyl) -tetrazole-5-

Free dimethylformamide is mixed with 1.4 g (0.01 mol) of sulfuryl thiomethyl] -3-cephem-4-carboxylic acid, trioxide-trimethylamine complex and then with a mixture of 1.89 g (0.064 mol) of disodium salt of

1.4 ml (0.01 mol) of triethylamine were added. The mixture is 65 l- (2-sulfaminoethyl) tetrazole-5-thiol and 2.67 g (0.064 mol)

Stirred for 1/2 hour and then filtered. The filtrate sodium salt of 7- (2-thienylacetamido) cephalosporan

is evaporated under reduced pressure. The acid obtained in 40 ml of water is heated to 69 ° C. for 5 hours,

Acetone is added to the residue. That after the Filfil- whereby the pH value by adding a dilute aqueous

Sodium bicarbonate solution is kept at 7.4.

After cooling, the mixture is extracted with ethyl acetate. The aqueous phase is neutralized and evaporated to dryness. The residue is passed through a column packed with XAD-4, eluting with water and methanol. The methanol is evaporated. After lyophilizing the aqueous residue, a solid product is obtained. This solid is suspended in methanol. The filtrate obtained after filtering off the insoluble material is evaporated to dryness. The diantrium salt of 7- (2-thienylacetamido) -3- [l- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid is obtained.

Ci7HnN707S4.2Na-l CH40 calc .: C 33.90 H 3.31 N 15.37 found: C 34.04 H 3.57 N 14.74

The disodium salt of 7- (2-thienylacetamido) -3- [1- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-car-bonic acid is converted to the title compound by the method of Example 1.

Example 3

7- (l-Tetrazolylacetamido) -3- [l- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

A mixture of 3.5 g (8.5 mmol) disodium salt of 7- (l-tetrazolylacetamido) cephalosporanic acid and 2.96 g (10 mmol) l- (2-sulfaminoethyl) tetrazole-5-thiol in 50 ml water is stirred for 6 hours at 65 ° C., the pH of the reaction mixture being kept at 7.0 by adding a percent aqueous sodium hydrogen carbonate solution. The mixture is then cooled to room temperature, acidified to pH 1.5 with 3N hydrochloric acid, filtered and extracted 3 times with ethyl acetate. The pH of the aqueous phase is then adjusted to 7.0 by adding sodium bicarbonate. The solution is chromatographed on a column packed with X AD-2. After freeze-drying the product obtained, the disodium salt of 7- (l-tetrazolylaceta-mido) -3- [l- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid is obtained.

C14H15N11O7S3.2Na.2H2O calc .: C 26.80 H 3.37 N 24.55 found: C 27.11 H 3.40 N 24.18

The disodium salt of 7- (l-tetrazolylacetamido) -3- [l- (2-suIfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-car-bonic acid is converted to the title compound by the method of Example 1.

Example 4

7-trifluoromethylthioacetamido-3- [1- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

A solution of 3.05 g (0.01 mol) disodium salt of 1- (2-sulfaminoethyl) tetrazole-5-thiol and 4.36 g (0.01 mol) sodium salt of 7-trifluoromethylthioacetamidocephalosporanic acid in 50 ml water is heated to 70 ° C. for 5 hours, the pH being kept at 7.5 with 5 percent aqueous sodium hydrogen carbonate solution. The reaction mixture is then diluted with 50 ml of water and extracted twice with ethyl acetate. The aqueous phase is acidified to pH 2 and extracted 3 times with ethyl acetate. The aqueous phase is brought to pH 7.4 by adding a 5 percent aqueous sodium hydrogen carbonate solution. Then the solution is over

627757

a column packed with XAD-4, using water and then methanol as eluent. The methanol solution is evaporated to dryness. The residue is dissolved in 75 ml of water. The aqueous solution is extracted twice with diethyl ether and petroleum ether and then lyophilized. The lyophilized material is dissolved in methanol. The residue obtained after evaporating the solvent to dryness is triturated with diethyl ether. The disodium salt of 7-trifluoromethyl-thioacetamido-3- [1- (2-sulfaminoethyl) -tetrazol-5-ylthio-methyl] -3-cephem-4-carboxylic acid is obtained.

C14H14F3O7S4.2Na.2H2O calc .: C 25.49 H 2.75 N 14.86 found: C 25.85 H 2.78 N 14.13

The disodium salt of 7-trifluoromethylthioacetamido-3- [1- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid is reacted according to the procedure of Example 1 to give the title compound.

Example 5

7- (D-a-Aminophenylacetamido) -3- [1- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

A solution of 7.58 g (0.015 mol) of 7- (Da-tert-butoxy-carbonylaminophenylacetamido) cephalosporanic acid, 2.96 g (0.01 mol) of disodium salt of l- (2-sulfaminoethyl) tetrazole-5- thiol and 1.26 g (0.015 mol) of sodium hydrogen carbonate in 125 ml of water are stirred for 5 hours at 60 ° C., the pH being kept at 7.0 to 7.2 by adding sodium hydrogen carbonate. The mixture is then cooled and extracted with ethyl acetate. The aqueous phase is acidified to pH 2.5 with 3N hydrochloric acid. The acidic solution is extracted again with ethyl acetate. The aqueous phase is brought to pH 7.1 by adding a percent sodium carbonate solution, then passed through a column packed with XAD-4 ion exchange resin and eluted with water and methanol. The disodium salt of 7- (D-a-tert-butoxycarbonylaminophenylacetamido) -3- [l- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] 3-cephem-4-carboxylic acid is obtained.

The disodium salt of 7- (Da-tert-butoxycarbonalamino-nophenylacetamido) -3- [l- (2-sulfominoethyl) -tetrazol-5-ylt-hiomethyl] -3-cephem-4-carboxylic acid is 2 'at 25 ° C / Stirred for 4 hours with 25 ml of trifluoroacetic acid and 25 ml of 1,3-dimethoxoxybenzene. The mixture is then evaporated to dryness. The residue is mixed with diethyl ether. The precipitate is collected, washed with diethyl ether, stirred in acetonitrile for 2 hours and dried under reduced pressure. The title compound is obtained in the form of its salt with trifluoroacetic acid.

An aqueous solution of this trifluoroacetic acid salt is brought to pH 5.0 by adding a dilute aqueous sodium hydroxide solution. The material obtained after lyophilization is dissolved in methanol. To precipitate the sodium salt of 7- (D-cc-aminophenylacetamido) -3- [l- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid, diethyl ether is added. The sodium salt is dissolved in water. The aqueous solution is passed through a column packed with Amberlite IR-120H ion exchange resin. After lyophilizing the eluted material, the title compound is obtained.

Example 6

The following compounds are obtained by reacting the N-tert-butoxycarbonyl derivatives of the following cephalosporanic acids:

7

s

10th

IS

20th

25th

30th

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627757

7- (a-amino-4-hydroxyphenylacetamido) cephalosporanic acid,

7- (a-Amino-4-formamidophenylacetamido) -cephalosporanic acid,

7 - («- Amino-3-formamidophenylacetamido) -cephalosporanic acid,

7- (a-Amino-4-ureidophenylacetamido) -cephalosporanic acid, 7- (a-Amino-3-ureidophenylacetamido) -cephalosporanic acid, 7- (ct-Amino-4-hydroxymethylphenylacetamido) -cephalospo-ranoic acid,

7- (a-Amino-1,4-cyclohexadienylacetamido) cephalosporanic acid, and

7- (a-Amino-4-carboxymethylaminophenylacetamido) cephalosporanic acid.

With the disodium salt of l- (2-sulfaminoethyl) -tetrazole-5-thiol according to Example 5, the following compounds are obtained after removal of the protective group and conversion of the trifluoroacetic acid salts to the free acids:

7- (a-amino-4-hydroxyphenylacetamido) -3- [l- (2-sulfamino-

ethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid,

7- (a-Amino-4-formamidophenylacetamido) -3- [l- (2-sulfamic

noethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid,

7- (a-Amino-3-formamidophenylacetamido) -3- [l- (2-sulfamic

noethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid,

7- (a-Amino-4-ureidophenylacetamido) -3- [l- (2-sulfamino-

ethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid,

7- (a-Amino-3-ureidophenylacetamido) -3- [l - (2-sulfamino-

ethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid,

7- (a-amino-4-hydroxymethylphenylacetamido) -3- [l - (2-sulf •

aminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carbon-

acid,

7- (a-Amino-1,4-cyclohexadienylacetamido) -3- [l - (2-sulfamic

noethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid and

7- (a-amino-4-carboxymethylaminophenylacetamido) -3- [l-

(2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-car-

bonic.

example 1

7- (4-Hydroxymandelic acid amido) -3- [l- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid is obtained by reacting the sodium salt of 7- (4-hydroxymandelic acid reamido) -cephalosporanoic acid and the disodium salt of l- (2-sulfaminoethyl) tetrazole-5-thiol with subsequent treatment of the product with Amberlite IR-120H ion exchange resin according to Example 1.

Example 8

By reacting the sodium salts of 7- (3-Sydnonace-tamidoj-cephalosporanic acid or 7- (2-aminomethylphenyl-acetamido) -cephalosporanic acid with the disodium salt of l- (2-sulfaminoethyl) -tetrazole-5-thiol according to Example 1 and converting the Product in the free acid gives 7- (3-sydnonacetamido) -3- [1- (2-sulfaminoethyl) -tetrazol-5-ylthio-methyl] -3-cephem-4-carboxylic acid or 7- (2-aminomethyl -phenylacetamido) -3- [1- (2-sulfaminoethyl) -tetrazol-5-ylthio-methyl] -3-cephem-4-carboxylic acid.

Example 9

By reacting the sodium salt of 7- (2,2,2-trifluoro-ethylthioacetamido) -cephalosporanic acid or 7-methyl-thioacetamidocephalosporanic acid with l- (2-sulfaminoethyl) -tetrazole-5-thiol according to Example 4, the salts are converted accordingly the free acids as end products 7- (2,2,2-trifluoroethylthioacetamido) -3 - [1 - (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-car-

bonic acid or 7-methylthioacetamido-3- [1- (2-sulfamino-ethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid.

Example 10

- s Using equivalent amounts of N- (3-aminopropyl) acetamide, N- (4-aminobutyl) acetamide or N- (5-aminopentyl) acetamide in the procedure of Example 1 instead of N- (2- Aminoethyl) acetamide and after treatment of the dithiocarbamates obtained with sodium azide, the corresponding 1-acetamidoalkyltetrazole-5-thiols are obtained, which are reacted according to Example 1 to give the corresponding 1-sulfaminoalkyl derivatives. The following 1-sulfaminoalkyltetrazole-5-thiols are obtained:

151 - (3-Sulfaminopropyl) -tetrazole-5-thiol, l- (4-sulfaminobutyl) -tetrazole-5-thiol or l- (5-sulfaminopentyl) -tetrazole-5-thiol.

By reacting the disodium salt one of the

2ohend listed l-sulfaminoalkyltetrazole-5-thiols with the sodium salt of 7-D-mandelic acid amidocephalosporanic acid according to Example 1 and with subsequent conversion of the salts formed to the free acids, the following compounds are obtained:

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7-D-mandelic acid amido-3- [1- (3-sulfaminopropyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid, 7-D-mandelic acid amido-3- [1- (4-sulfaminobutyl) tetrazole -5-ylthiomethyl] -3-cephem-4-carboxylic acid or

30 7-D-Mandelic acid amido-3- [1- (5-sulfaminopentyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid.

Similarly, by reacting substituted tetrazole thiols or the corresponding disodium

35 salts with the listed 7-acylcephalosporanic acids or their salts according to the processes described the corresponding compounds of the invention.

Example 11

40 The following compounds are obtained by reacting the cephalo-sporanic acids listed below or their corresponding salts:

7- (a-Hydroxy-2-thienylacetamido) cephalosporanic acid, 45 7- (a-carboxy-2-thienylacetamido) cephalosporanic acid and 7- (cc-sulfophenylacetamido) cephalosporanic acid.

With the disodium salt of l- (2-sulfaminoethyl) tetrazole-5-thiol according to the above-mentioned processes, the following compounds are obtained after conversion of the product into the free acid:

7- (a-Hydroxy-2-thienylacetamido) -3- [l- (2-suIfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid, 55 7- (a-carboxy-2-thienylacetamido) -3- [l- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid or 7- (a-Sulfophenylacetamido) -3- [1- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid.

see example 12

7a-methoxy-7ß- (2-thienylacetamido) -3- [l- (2-sulfamino-ethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

A solution of 1.28 g (3 mmol) of sodium salt of 7a-methoxy-7β- (2-thienylacetamido) cephalosporanic acid in 65 50 ml of water is mixed with 1.33 g (4.5 mmol) of disodium salt of 1- (2-sulfaminoethyl) ) -tetrazole-5-thiol added. The solution is heated to 70 ° C. until the consumption of the starting material can be demonstrated by thin layer chromatography

leaves (about 5 hours). The reaction mixture is then chromatographed on XAD-4 ion exchange resin, washing first with water and then using methanol as the eluent. After evaporating the methanol solution, the title compound is obtained in the form of its disodium salt.

The disodium salt of 7a-methoxy-7β- (2-thienylacet-amido) -3- [l- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid becomes the title according to the procedure explained above Connection implemented.

Example 13

7oc-methoxy-7ß-trifluoromethylthioacetamido-3- [1- (2-sulfo-aminoethyl) -tetrazol-5-ythiomethyl] -3-cephem-4-carboxylic acid

A cold solution of 5.25 g (0.012 mol) of 7ß-amino-7a-methoxycephalosporanic acid benzhydryl ester in 200 ml of methylene chloride containing 1.79 g (0.012 mol) of N, N-diethylaniline is added dropwise within 20 minutes with a Solution of 1.82 g (0.012 mol) of trifluoromethyl-ylthioacetyl chloride in 50 ml of methylene chloride. After stirring for 30 minutes, the mixture is extracted successively with a 5 percent aqueous sodium hydrogen carbonate solution, with 5 percent aqueous hydrochloric acid and finally with saline. The organic phase is dried over MgSÜ4. After evaporation of the solvent, 7a-methoxy-7β-trifluoromethyl-thioacetamidocephalosporanoic acid benzhydryl ester is obtained.

7a-methoxy-7ß-trifluoromethylthioacetamidocephalospo-ransäurebenzhydrylester is dissolved in a cold mixture of trifluoroacetic acid and anisole (2: 1). The mixture is then stirred for 1 1/2 hours without external cooling. The residue obtained after evaporating the solvent under reduced pressure is taken up in ethyl acetate, washed with water, dried over MgSCU and concentrated to a small volume under reduced pressure. The solution obtained is added dropwise to petroleum ether with stirring. 7a-methoxy-7β-trifluoromethylthioacetamidocephalosporanic acid precipitates out.

2.2 g (5 mmol) of 7a-methoxy-7β-trifluoromethylthioacetamido-docephalosporanic acid are suspended in 75 ml of water. Then 0.4 g of solid sodium bicarbonate is added until a complete solution is reached. 2.21 g (7.5 mmol) of disodium salt of 1- (2-sulfamino-ethyl) -tetrazole-5-thiol are added to the solution. The mixture is heated to 70 ° C for 7 hours. The pH of the reaction mixture is kept at 7.5 as required by dropwise addition of 3N hydrochloric acid. The progress of the reaction is recorded by thin layer chromatography. The reaction is considered to be complete as soon as the thin-layer chromatographic evidence shows that the starting material has disappeared. The reaction mixture is then treated with XAD-4 resin by column chromatography. The product is eluted from the column with methanol. After evaporation of the methanol solution, the disodium salt of 7a-meth-oxy-7β-trifluoromethylthioacetamido-3- [l- (2-sulfamino-ethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid is obtained.

The disodium salt is converted to the title compound in the manner explained above.

Example 14

7β-D-mandelic acid amido-7a-methoxy-3- [1- (2-sulfamino-ethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

A cold solution of 2.6 g (6 mmol) of 7ß-amino-7a-met-hoxycephalosporansäure-benzhydrylesterin 100 ml of methylene chloride containing 0.9 g (6 mmol) of N, N-diethyl-aniline is added within 15 minutes dropwise with a solution of 1.7 g (6 mmol) of DO-dichloroacetylmandelic acid

627757

rechloride treated in 25 ml methylene chloride. The reaction mixture is warmed to room temperature with stirring and then extracted successively with a 5% aqueous sodium hydrogen carbonate solution, 5% hydrochloric acid and hydrochloric acid. The organic phase is dried and evaporated under reduced pressure. The residue is dissolved in a cooled mixture of trifluoroacetic acid and anisole (2: 1) and stirred for 1 hour at ambient temperature. The mixture is then evaporated under reduced pressure. The residue obtained is dissolved in a 5 percent aqueous sodium hydrogen carbonate solution. The pH is increased to 9 to 9.3 by adding a 5 percent aqueous sodium carbonate solution and held in this range for 30 minutes in order to complete the elimination of the dichloroacetyl group. The solution is then cooled in ice, overlaid with ethyl acetate and acidified to pH 2.0 with dilute hydrochloric acid. After the phases have been separated, the aqueous phase is extracted a second time with ethyl acetate. The organic phases are combined, dried and evaporated under reduced pressure. 7β-D-Mandelic acid amido-7a-methoxy-cephalosporanic acid is obtained.

2.2 g (5 mmol) of 7β-D-mandelic acid amido-7a-methoxyce-phalosporanic acid are suspended in 75 ml of water. Solid sodium hydrogen carbonate is added to the suspension until the acid has completely dissolved. 2.21 g (7.5 mmol) of disodium salt of 1- (2-sulfaminoethyl) -tetrazole-5-thiol are added to the solution obtained. The mixture is heated to 70 ° C for 7 hours. The pH of the reaction mixture is kept at 7.5 by adding 3N hydrochloric acid. After chromatography of the solution obtained on XAD-4 resin, eluting with methanol and after evaporating the methanol, the title compound is obtained in the form of its disodium salt.

The disodium salt of 7β-D-mandelic acid amido-7a-met-hoxy-3- [1- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid is converted to the title compound in the manner explained above.

Example 15

7 "-Methoxy-7ß- (D-a-aminophenylacetamido) -3- [l - (2-sul f-aminoethyl) -tetrazol-5-ylthiomethyI] -3-cephem-4-carboxylic acid

A solution of 5.3 g (0.012 mol) of 7β-amino-7a-methoxy-cephalosporanoic acid p-nitrobenzyl ester in 200 ml of methylene chloride is mixed with 3.0 g (0.012 mol) of Da-tert-butoxycarbonylaminophenyl acetic acid and 2, 5 g (0.012 mol) of dicylo-xylcarbodiimide were added. The mixture is stirred at ambient temperature for 18 hours and then filtered. The filtrate is evaporated under reduced pressure. The residue obtained is dissolved in a mixture of methanol and tetrahydrofuran and hydrogenated over 5 percent palladium-on-carbon. 7ß- (D-a-tert-Butoxy-carbonylaminophenylacetamido) -7a-methoxycephalospo-ranoic acid is obtained.

2.68 g (5 mmol) of 7β- (D-cc-tert-butoxycarbonylaminophenylacetamido) -7a-methoxyphalosporanic acid are dissolved in 75 ml of water with the addition of 0.4 g of solid sodium hydrogen carbonate. 2.21 g (7.5 mmol) of disodium salt of 1- (2-sulfaminoethyl) -tetrazole-5-thiol are added to the solution. The reaction mixture is heated to 70 ° C until thin layer chromatographic analysis indicates that the starting material has disappeared.

The reaction mixture is then chromatographed on XAD-4 resin, eluting with methanol. After evaporation of the methanol solution, the disodium salt of 7a-methoxy-7ß- (D-cc-tert.-butoxycarbonylamino-

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phenylacetamido) -3- [1- (2-sulfaminoethyl) tetrazol-5-ylthio-methyl] -3-cephem-4-carboxylic acid.

The disodium salt is suspended in a 1: 1 mixture of trifluoroacetic acid and anisole and stirred for 2 hours at ambient temperature. Excess trifluoroacetic acid is removed by evaporation. The residue obtained is triturated with diethyl ether. The precipitate is filtered off and stirred with acetonitrile. The title compound is obtained in the form of its salt with trifluoroacetic acid.

An aqueous solution of this trifluoroacetic acid salt is brought to pH 7 by adding a percent aqueous sodium bicarbonate solution and then chromatographed on XAD-4 resin using methanol as eluent. The solid product obtained after evaporating the methanol is dissolved in water. The aqueous solution is passed over a cation exchange resin (IR-120H). After the lyophili-

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the eluted material, the title compound is obtained.

Example 16

7a-methoxy-7ß- (l-tetrazolylacetamido) -3- [l- (2-sulfamino-5 ethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

If a corresponding amount of 1-tetra-zolylacetyl chloride is used in the process of Example 13, 7a-methoxy-7β- (l-tetrazolylacetamido) -cephalosporanic acid benzhydryl ester is obtained which, according to the procedure described, leads to 7a-methoxy-7ß - (l-Tetrazolylacetamido) -cephalo-sporanoic acid is implemented.

By converting 7a-methoxy-7ß (l-tetrazolylaceta-mido) cephalosporanic acid, the disodium salt of 1 - (2-sulfaminoethyl) tetrazol-5-thiol and sodium hydrogen carbonate 15 according to Example 13, the resulting disodium salt is converted into the free acid the title compound according to the procedure described above.

B

Claims (13)

627757 e.g. PATENT CLAIM 1. Process for the preparation of new cephalosporin derivatives of the general formula I H W 1 1 E R-N (I) in the W is a hydrogen atom or the methoxy group and R1 is one of the acyl radicals O II X-CH-C-, 1 A O II Y-CH2-C- or O Z-S means (0) m-CH2-C-, where X represents a thienyl, dihydrophenyl, phenyl or phenyl radical monosubstituted by a hydroxyl, hydroxymethyl, formamido, ureido or carboxymethylamino group, A -NH2, -OH, -COOH or -SCbH or, if X represents the phenyl group, represents the formyloxy group, Y represents a thienyl, tetrazolyl, Sydnon, cyano or amino-methylphenyl group, Z represents a methyl, trifluoromethyl, trifluoroethyl, cyano-methyl or pyridyl group, m has the value 0.1 or 2 and n has the value 2, 3, 4 or 5, and their salts, characterized in that a compound of the general formula H I ü R1 - ^ - ^ s 50 • (CH.) -NHSO-H £. n 'j 15 in which n has the meaning given above, or its salt, optionally converted into the free acid and optionally converting the product into a salt with an acid. 2. The method according to claim 1, characterized in that n has the value 2. 3. The method according to claim 1, characterized in that R1 does the rest O 25 X-CH-C-, A X represents a phenyl group and A represents -NH2 or -OH. 30 4. The method according to claim 1, characterized in that R1 the rest 40 0 ^ ~ N. II H2OCCH3 (II) COOH in the R1 and W have the meaning given above or their salt with a compound of the general formula -N ss 60 (III) • N 65 O Y-CH2-C- and Y represents a thienyl or tetrazolyl group. 5. The method according to claim 1, characterized in that R1 the rest O 45 (CH ^ -NHSO-jH Z-S (0) m-CH2-C-, Z represents the trifluoromethyl group and m has the value 0 to 2. 6. The method according to claim 1, characterized in that 7-mandelic acid amido-3- [l- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid by reaction of the sodium salt of 7-mandelic acid amidoce- phalosporanic acid with the disodium salt of l- (2-sulfamino-ethyl) -tetrazole-5-thiol and subsequent acidification. 7. The method according to claim 1, characterized in that by 7ß-mandelic acid amido-7a-methoxy-3- [l- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carbon-acid by Implementation of 7ß-mandelic acid amido-7a-meth-oxycephalosporanic acid, sodium hydrogen carbonate and the disodium salt of l- (2-sulfaminoethyl) -tetrazol-5-thioI and subsequent conversion into the free acid. 8. The method according to claim 1, characterized in that 7- (2-thienylacetamido) -3- [l- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid by reaction of 7- (2-Thienylacetamido) -cephalosporanoic acid with the disodium salt of l- (2-sulfaminoethyl) -tetrazole-5-thiol and subsequent conversion into the free acid. 9. The method according to claim 1, characterized in that 7- (l-tetrazolylacetamido) -3- [l- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid by reacting the sodium salt of 7- (l-Tetrazolylacet-amido) -cephalosporanoic acid with the disodium salt of l- (2-sulfaminoethyl) -tetrazole-5-thiol and subsequent acidification. 10. The method according to claim 1, characterized in that 7a-methoxy-7ß- (2-thienylacetamido) -3- [l- (2-suIf-aminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4- carbonic acid by reacting the sodium salt of 7a-methoxy-7ß- (2-thienylacetamido) -cephalosporanoic acid with the disodium salt of l- (2-sulfaminoethyl) -tetrazole-5-thiol and then converting it to the free acid. 11. The method according to claim 1, characterized in that 7a-methoxy-7ß- (l-tetrazolylacetamido) -3- [l- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-car- producing bonic acid by reacting 7a-methoxy-7ß- (l-tetra-zolyl-acetamido) cephalosporanic acid, sodium hydrogen carbonate and the disodium salt of l- (2-sulfaminoethyl) -tetrazole-5-thiol and then converting it to the free acid. 12. The method according to claim 1, characterized in that 7-trifluoromethylthioacetamino-3- [l- (2-sulfamino- 3 627757 ethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid by reacting the disodium salt of 7-trifluorometh-ylthioacetamidocephalosporanic acid with the disodium salt of l- (2-sulfaminoethyl) -tetrazole-5-thiol and then connecting 5-sansanes manufactures. 13. The method according to claim 1, characterized in that by 7a-methoxy-7ß-trif! Uormethylthioacetamido-3- [l- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3-cephem-4-car-bonic acid Implementation of 7a-methoxy-7ß-trifluorme- 10 Thylthioacetamidocephalosporansäure, sodium bicarbonate and the disodium salt of l- (2-sulfaminoethyl) -tetrazole-5-thiol and then converting to the free acid. 14. Use of a new cephalosporin derivative of the general formula I for the preparation of a corresponding ester by esterifying the carboxyl group in the 4-position and optionally the carboxyl group represented by the symbol A.